Macica Carolyn M, von Hehn Christian A A, Wang Lu-Yang, Ho Chi-Shun, Yokoyama Shigeru, Joho Rolf H, Kaczmarek Leonard K
Department of Pharmacology, Yale University, New Haven, Connecticut 06520, USA.
J Neurosci. 2003 Feb 15;23(4):1133-41. doi: 10.1523/JNEUROSCI.23-04-01133.2003.
Neurons of the medial nucleus of the trapezoid body, which transmit auditory information that is used to compute the location of sounds in space, are capable of firing at high frequencies with great temporal precision. We found that elimination of the Kv3.1 gene in mice results in the loss of a high-threshold component of potassium current and failure of the neurons to follow high-frequency stimulation. A partial decrease in Kv3.1 current can be produced in wild-type neurons of the medial nucleus of the trapezoid body by activation of protein kinase C. Paradoxically, activation of protein kinase C increases temporal fidelity and the number of action potentials that are evoked by intermediate frequencies of stimulation. Computer simulations confirm that a partial decrease in Kv3.1 current is sufficient to increase the accuracy of response at intermediate frequencies while impairing responses at high frequencies. We further establish that, of the two isoforms of the Kv3.1 potassium channel that are expressed in these neurons, Kv3.1a and Kv3.1b, the decrease in Kv3.1 current is mediated by selective phosphorylation of the Kv3.1b isoform. Using site-directed mutagenesis, we identify a specific C-terminal phosphorylation site responsible for the observed difference in response of the two isoforms to protein kinase C activation. Our results suggest that modulation of Kv3.1 by phosphorylation allows auditory neurons to tune their responses to different patterns of sensory stimulation.
梯形体内侧核的神经元负责传递用于计算声音在空间中位置的听觉信息，它们能够以很高的时间精度在高频下放电。我们发现，敲除小鼠体内的Kv3.1基因会导致钾电流的高阈值成分丧失，并且神经元无法跟随高频刺激。通过激活蛋白激酶C，可以使梯形体内侧核的野生型神经元中的Kv3.1电流部分降低。矛盾的是，蛋白激酶C的激活会提高时间保真度以及由中等频率刺激诱发的动作电位数量。计算机模拟证实，Kv3.1电流的部分降低足以提高中等频率下的反应准确性，同时损害高频反应。我们进一步确定，在这些神经元中表达的Kv3.1钾通道的两种亚型Kv3.1a和Kv3.1b中，Kv3.1电流的降低是由Kv3.1b亚型的选择性磷酸化介导的。使用定点诱变，我们确定了一个特定的C末端磷酸化位点，该位点导致了两种亚型对蛋白激酶C激活反应的差异。我们的结果表明，通过磷酸化对Kv3.1进行调节可使听觉神经元调整其对不同感觉刺激模式的反应。
